Activation of the ERK1/2 mitogen-activated protein kinases (MAPK) confers resistance to the RAF inhibitors vemurafenib and dabrafenib in mutant BRAF-driven melanomas. Methods to understand how resistance develops are important to optimize the clinical use of RAF inhibitors in patients. Here, we report the development of a novel ERK1/2 reporter system that provides a noninvasive, quantitative, and temporal analysis of RAF inhibitor efficacy in vivo. Use of this system revealed heterogeneity in the level of ERK1/2 reactivation associated with acquired resistance to RAF inhibition. We identified several distinct novel and known molecular changes in resistant tumors emerging from treatment-naïve cell populations including BRAF V600E variants and HRAS mutation, both of which were required and sufficient for ERK1/2 reactivation and drug resistance. Our work offers an advance in understanding RAF inhibitor resistance and the heterogeneity in resistance mechanisms, which emerge from a malignant cell population.

In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors / K. J., Basile; E. V., Abel; N., Dadpey; E. J., Hartsough; Fortina, Paolo; A. E., Aplin. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 73:23(2013), pp. 7101-7110. [10.1158/0008-5472.can-13-1628]

In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors.

FORTINA, PAOLO;
2013

Abstract

Activation of the ERK1/2 mitogen-activated protein kinases (MAPK) confers resistance to the RAF inhibitors vemurafenib and dabrafenib in mutant BRAF-driven melanomas. Methods to understand how resistance develops are important to optimize the clinical use of RAF inhibitors in patients. Here, we report the development of a novel ERK1/2 reporter system that provides a noninvasive, quantitative, and temporal analysis of RAF inhibitor efficacy in vivo. Use of this system revealed heterogeneity in the level of ERK1/2 reactivation associated with acquired resistance to RAF inhibition. We identified several distinct novel and known molecular changes in resistant tumors emerging from treatment-naïve cell populations including BRAF V600E variants and HRAS mutation, both of which were required and sufficient for ERK1/2 reactivation and drug resistance. Our work offers an advance in understanding RAF inhibitor resistance and the heterogeneity in resistance mechanisms, which emerge from a malignant cell population.
2013
01 Pubblicazione su rivista::01a Articolo in rivista
In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors / K. J., Basile; E. V., Abel; N., Dadpey; E. J., Hartsough; Fortina, Paolo; A. E., Aplin. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 73:23(2013), pp. 7101-7110. [10.1158/0008-5472.can-13-1628]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/556796
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